Parenteral delivery and collection of medical fluids are important factors in current medical care. Such fluids are delivered principally via intravenous and intraperitoneal routes, while phlebotomy constitutes the major collection modality. Intravenous fluids commonly include blood and blood fractions, sugar, electrolyte and osmotic solutions, and nutrient preparations. Fluids are generally delivered intraperitoneally to remove excreted nitrogenous wastes from end stage renal disease patients in a process known as peritoneal dialysis.
Many beneficial and therapeutic agents are preferably delivered via parenteral fluids to avoid digestive tract and liver associated modification of those agents. Historically such agents have been formulated and added to the parenteral fluid reservoir by a pharmacist or nurse. Because this is a labor intensive step with opportunity for error, and because many beneficial agents are less stable in solution than in dry form, systems have been developed to facilitate formulation of soluble dry agents with parenteral fluid immediately before use. One such system disclosed in U.S. Pat. No. 4,614,267 still requires manual formulation.
The next advance provided preprogrammed, unattended systems to formulate parenteral fluid with soluble dry agents in situ in a formulation chamber associated with the primary delivery set. An example of such a system is disclosed in U.S. Pat. No. 4,552,555 in which the beneficial agent is contained within a formulation chamber bounded by a membrane. The membrane serves to control the delivery rate of beneficial agent into the flowing stream of medical fluid. Controlled delivery of a beneficial agent into a medical fluid can also be achieved through diffusion of the agent from a non-erodible polymer matrix that contains and serves as a reservoir of the agent. Generally the permeability of the matrix controls the diffusion rate of the agent into the surrounding environment. Such systems are described in U.S. Pat. Nos. 3,921,636 and 4,511,353. When a membrane or matrix system is used to control beneficial agent delivery into parenteral fluids, actual delivery rate of the agent to the patient is substantially independent of fluid flow rate; a benefit if adequate fluid flow control means are not available. However, that same flow rate independence restricts the ability of the healthcare professional to increase dose rate to meet patient needs. While such inventions have improved the efficiency and safety of administering beneficial agents to parenteral fluids, they fall short of the ideal: (1) by not providing a clear visual indication that the dose has been delivered; 2) by causing a major portion of the beneficial agent in the formulation chamber to dissolve in the parenteral fluid early in the delivery procedure, thereby leaving the agent in solution for the extended period of time required to deliver the dose; and, (3) by requiring that the agent for formulation be present in a form which is soluble in the parenteral fluid.
The ideal system for parenteral or blood delivery would be a matrix that contains and/or protects, as necessary, one or more entrapped beneficial agents in a dry, stable state; that, when placed in a flow chamber in the medical fluid administration line, disappears as the agent is delivered into the flowing stream, indicating delivery of the dose. The simplest means of effecting disappearance is dissolution of the matrix in the stream of medical fluid, thereby releasing the entrapped agent. This suggests the matrix should be formed from innocuous components clinically acceptable for use in parenteral fluids and could be the beneficial agent itself or a component thereof, a beneficial metabolite, or a non-toxic excretable molecule.
Preferably, the matrix would dissolve proportionally to the flow of medical fluid over its surface with its dissolution rate determining the delivery rate of the beneficial agent; thus allowing the beneficial agent to remain stable and protected within the matrix until both matrix and agent become hydrated and dissolve. The dissolution rate of the beneficial agent should match or exceed the dissolution rate of the matrix; otherwise the matrix could dissolve away leaving the beneficial agent as an insoluble mass in the flowing fluid.
Since the most stable forms of many drugs are not directly soluble in water or saline, it would be advantageous to use them as the storage form in the matrix, co-entrapped with dry modifying agents, such as pH buffers or solubilizing reactants, under conditions that they neither react with each other during the formation of the matrix nor during storage, but such that when the dissolving fluid reaches the beneficial agent, it will have dissolved sufficient pH buffer or reactant to create a localized environment in the fluid boundary layer that favors dissolution of the otherwise insoluble beneficial agent.
A similar rationale leads to matrix compositions that deliver active agents from inactive storage forms co-entrapped with their activator species; or, as examples of other variations, beneficial agents in their active forms co-entrapped with inhibitors of enzymes that would inactivate the agents, and, initial release of a beneficial agent followed in time by the release of its inactivator. The latter case may be achieved, for example, by forming the matrix with the separate agents in defined concentric layers. The matrix may also serve as a separator of mutually reactive species. In such a case, the matrix must be appropriately inert in a chemical sense towards the beneficial agents and the reactants associated with them.
In summary, controlled dissolution operates at five different levels to provide controlled administration of beneficial agents to flowing medical fluids: (1) the flow field of the medical fluid in conjunction with the shape of the solid matrix element, (2) the dissolution properties of the matrix material, (3) the geometric distribution pattern of beneficial agent and modifying agent particles within the matrix, (4) the dissolution properties and size of beneficial agent and modifying agent particles, and (5) the chemical/solubilizing interactions between beneficial agents and modifying agents at the solid/fluid interface.
While each beneficial agent or combination of such agents may require individual adjustment for optimum matrix composition and method of formation, general principles are available. It is well known that essential oils with extreme sensitivity to heat, light, air and moisture can be stabilized for storage in dry form by encapsulation in dry sugar melts using methods disclosed by Swisher in U.S. Pat. Nos. 2,809,895 and 3,041,180. Similarly, therapeutic activity of heat sensitive beneficial agents can be preserved by incorporating them at moderate temperatures into a cooling melt of the embedding matrix using standard candy manufacture methods such as those disclosed by Mozda in U.S. Pat. No. 4,753,800. Sair, in choosing a protective and stabilizing matrix material for encapsulated food additives, disclosed in U.S. Pat. No. 4,232,047 that mustard oil was less reactive with a matrix composed of polymeric carbohydrate than with a protein matrix. Analogous reasoning when choosing initial matrix materials for parenteral fluids might suggest use of non-reducing monomeric carbohydrates. Water may be the most chemically active molecule in a matrix, and stability of certain beneficial agents could require rigorous exclusion of reactive water from their encapsulating matrix, even below the 0.5 to 2.0% water content values considered virtually anhydrous by Swisher in U.S. Pat. No. 3,041,180.